Myocardial perfusion imaging (MPI) is a diagnostic technique useful for the detection and characterization of coronary artery disease. Perfusion imaging uses materials such as radionuclucides to identify areas of insufficient blood flow. In MPI, blood flow is measured at rest, and the result compared with the blood flow measured during exercise on a treadmill (cardiac stress testing), such exertion being necessary to stimulate blood flow. Unfortunately, many patients are unable to exercise at levels necessary to provide sufficient blood flow, due to medical conditions such as peripheral vascular disease, arthritis, and the like.
Therefore, a pharmacological agent that increases CBF for a short period of time would be of great benefit, particularly one that did not cause peripheral vasodilation. Vasodilators, for example dipyridamole, have been used for this purpose in patients prior to imaging with radionuclide. Dipyridamole is an effective vasodilator, but side effects such as pain and nausea limit the usefulness of treatment with this compound.
Adenosine, a naturally occurring nucleoside, also is useful as a vasodilator. Adenosine exerts its biological effects by interacting with a family of adenosine receptors characterized as subtypes A1, A2A, A2B, and A3. AdenoScan® (Fujisawa Healthcare Inc.) is a formulation of a naturally occurring adenosine. AdenoScan has been marketed as an adjuvant in perfusion studies using radioactive thallium-201. However, its use is limited due to side effects such as flushing, chest discomfort, the urge to breathe deeply, headache, throat, neck, and jaw pain. These adverse effects of adenosine are due to the activation of other adenosine receptor subtypes in addition to A2A, which mediates the vasodilatory effects of adenosine. Additionally, the short half-life of adenosine necessitates multiple treatments during the procedure, further limiting its use. AdenoScan is contraindicated in many patients including those with second-or third-degree block, sinus node disease, bronchoconstructive or bronchospastic lung disease, and in patients with known hypersensitivity to the drug.
Other potent and selective agonists for the A2A adenosine receptor are known. For example, MRE-0470 (Medco) is an adenosine A2A receptor agonist that is a potent and selective derivative of adenosine. WRC-0470 (Medco) is an adenosine A2A agonist used as an adjuvant in imaging. These compounds, which have a high affinity for the A2A receptor, and, consequently, a long duration of action, which is undesirable in imaging.
Thus, there is still a need for a method of producing rapid and maximal coronary vasodilation in mammals without causing corresponding peripheral vasodilation, which would be useful for myocardial imaging with radionuclide agents. Preferred compounds would be selective for the A2A adenosine receptor and have a short duration of action (although longer acting than compounds such as adenosine), thus obviating the need for multiple dosing.
Selective A2A receptor agonists are well known; for example, see Provisional Patent Application Ser. Nos. 60/184,4296 and 60/21987. The compounds disclosed therein have a high specificity for the adenosine A2A receptor subtype but are not necessarily selective to heart. We have discovered a method for identifying A2A receptor agonists that produce the desired vasodilation in the heart but do not significantly affect the peripheral vasculature and have a short duration of action.
In addition to discovering a method to identify A2a agonists that are selective coronary vasodilators, we have discovered that compounds that meet our criteria that would be superior as adjuncts to MPI techniques.
Additionally, in the above-identified Provisional Patent Application Ser. Nos. 60/184,4296 and 60/219,876 the effective dose of the compounds of is disclosed to be in the range of 0.01-100 mg/kg/day. Surprisingly, we have discovered that the compounds are active at much lower doses (0.0002-0.009 mg/kg) than those disclosed as effective in Accordingly, a novel and effective method of using the compounds is provided, which is virtually free of undesirable side effects.